Cellular proliferative disorders such as cancer are among the most common causes of death in developed countries. That said, many cellular proliferative disorders have no available cures or few, if any, treatment options to slow the progression of the disease. For cellular proliferative diseases for which treatments exist, undesirable side effects and limited efficacy often call into question the utility of a given treatment. This is particularly true when the available treatment option(s) may not appreciably prolong life, but have a definitive adverse effect on the quality of time remaining. Thus, identifying new effective drugs for cellular proliferative disorders, and in particular cancer, is a continuing focus of medical research.
Pim-1
Pim-1 is a proto-oncogene which encodes for a serine/threonine. Pim-1 over-expression has been implicated in multiple human cancers, including prostate cancer, acute myeloid leukemia and other hematopoietic malignancies. Pim-1 has also been found to be highly expressed in cell cultures isolated from human tumors and is mainly involved in cell cycle progression, apoptosis and transcriptional activation, as well as more general signal transduction pathways (Bachmann and Möröy, Int. J. Biochem. Cell Biol. 37(4):726-30 (2005)). Compounds that inhibit the activity of Pim-1 have potential as anticancer agents.
CK2 and CDK9
Casein Kinase 2 (CK2) is a ubiquitously expressed serine threonine protein kinase, whose activity and expression levels are elevated in a variety of tumor types (St-Denis and Litchfield, Cell. Mol. Life Sci., 66:1817-1829 (2009); Trembley et al., Cell. Mol. Life Sci., 66:1858-1867 (2009)). CK2 is unusual among protein kinases in that it can use both ATP and GTP as phosphate donors (St-Denis and Litchfield, supra). CK2 is also unique in that it is constitutively active and does not appear to require phosphorylation or other post-translational alterations to activate its kinase activity. As a result, the catalytic activity of CK2 is roughly proportional to its cellular concentration (Guerra and Issinger, Curr. Med. Chemistry, 15: 1870-1886 (2008)). CK2 is a tetrameric complexes consisting of two catalytic (α and/or α′) subunits and two regulatory β subunits (Litchfield, Biochem. J. (2003) 369:1-15).
CK2 phosphorylates a large number of substrates, many of which regulate signal transduction pathways that in turn mediate cell growth, cell death, DNA replication and transcription (St-Denis and Litchfield, supra; Trembley et al., supra; Guerra and Issinger, supra). CK2 has also been shown to regulate the activity of tumor suppressors, cell cycle regulatory proteins, apoptotic proteins and oncogenes thus making it a key player in the development and maintenance of cancer progression (Ahmed et al., Cellular and Molecular Life Sciences, 66: 1858-1867 (2009)).
Elevated CK2 activity has been associated with the malignant transformation of several tissues and higher levels of CK2 are found to correlate with aggressive behavior of head and neck cancer and poor prognosis of prostate cancer (Gapany et al., Mol. Med. 1: 659-666 (1995); Laramas et al., Eur. J. Cancer. 43(5):928-34 (2007)). The ability of CK2 to phosphorylate (and activate) PTEN and AKT, two key components of tumor cell survival pathway, suggests an important role of CK2 in suppressing apoptosis in cancer cells (Di Maira et al., Cell Death Differ. 12: 668-677 (2005)). Downregulation of CK2 by various approaches results in induction of apoptosis in cultured cell and xenograft cancer models, further suggesting its potential as a therapeutic target (Guerra and Issinger, supra; Ruzzene and Pinna, Biochim Biophys Acta, 1804(3): 499-504 (2010)).
Normal cells, which express low levels of CK2, do not appear to have such undue reliance on the activity of this kinase and hence are unaffected by reduction in the levels of this kinase activity, suggesting that development of potent and selective CK2 inhibitors may not exhibit undesirable side effects seen with traditional chemotherapeutic agents.
CDK9 is a cyclin-dependent kinase, which forms a complex with and is regulated by two different regulatory cyclins known as cyclin T and cyclin K (Wang and Fischer, Trends Pharmacol. Sci. 29(6):302-13 (2008)). CDK9 accumulates on chromatin and limits the amount of single-stranded DNA in response to replication stress. CDK9/Cyclin K complex was found to play direct role in maintaining genome integrity (Yu and Cortez, Cell Cycle 10:1, 28-32 (2011)).
Depletion of CDK9 or its cyclin K (but not cyclin T) was found to impair cell cycle recovery in response to replication stress, resulting in spontaneous DNA damage in replicating cells (Wang et al., supra; Yu et al., EMBO Rep. 11(11):876-82 (2010)).
CDK9 is over-expressed in several cancers, including leukemias and lymphomas suggesting that inhibitors might be useful in cancers involving high levels of replication stress, or in combination with replication stress-inducing chemotherapies (Wang and Fischer, supra).